2012 genitourinary con

Genitourinary Cancers

CCO Independent Conference Coverage
of the 2012 Genitourinary Cancers Symposium*
February 2-4, 2012
San Francisco, California
*CCO is an independent medical education company that
provides state-of-the-art information to healthcare
*CCO is an independent medical education company that
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2012 Genitourinary Cancers Symposium: Highlights
clinicaloptions.com/oncology

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Faculty
Daniel P. Petrylak, MD
Professor of Medicine
Columbia University Medical Center
Herbert Irving Cancer Center
New York, New York

David I. Quinn, MD, PhD
Associate Professor of Medicine
Division of Cancer Medicine and Blood Diseases
The University of Southern California
Medical Director, USC Norris Cancer Hospital and Clinics
Los Angeles, California


Faculty Disclosures
Daniel P. Petrylak, MD, has disclosed that he has
participated on advisory boards or as a consultant for
Amgen, AstraZeneca, Bellicum, Dendreon, Egenix, Ferring,
Johnson & Johnson, Millennium, Novartis, and Otsuka; has
received research support from Abbott, Boehringer
Ingelheim, Celgene, Dendreon, Eisai, GlaxoSmithKline,
Johnson & Johnson, Medivation, Pfizer, Progenics, and
sanofi-aventis, and has served as a board member on the
Prostate Conditions Education Council.
David I. Quinn, MD, PhD, has disclosed that he has
received consulting fees from AVEO, Bayer, Dendreon,
Medivation, Novartis, Onyx, and Pfizer.


Overview
 Prostate cancer
 Renal cell carcinoma
 Testicular cancer
 Urothelial cancer


AFFIRM: Phase III Trial of MDV3100 in
Post-Docetaxel CRPC
Study stopped at planned interim analysis at
520 events with observation of statistically
significant, clinically meaningful OS benefit
Randomized 2:1

MDV3100 160 mg/day
(n = 800)
Patients with progressive
CRPC who failed docetaxel Stratified by ECOG PS and Mean Brief Pain
chemotherapy Inventory question 3 score

(N = 1199)
Placebo
(n = 399)
 Primary endpoint: OS
 Secondary endpoints:
– Response: PSA response, STOR, QoL, pain palliation, CTC
– Progression: radiographic PFS, time to PSA progression, time to first SRE

Scher HI, et al. ASCO GU 2012. Abstract LBA1.


AFFIRM Trial of MDV3100 in Post-
Docetaxel CRPC: OS
 OS improved with MDV3100 vs placebo
 Median follow-up: 14.4 mos
HR: 0.631 (95% CI: 0.529-0.752; P < .0001)
100 37% reduction in risk of death
90
80 MDV3100: 18.4 mos
70 (95% CI: 17.3-NR)
Survival (%)

60
50
40
30
20 Placebo: 13.6 mos
(95% CI: 11.3-15.8)
10
0
0 3 6 9 12 15 18 21 24
Duration of OS (Mos)
MOV3100 800 775 701 627 400 211 72 7 0
Placebo 399 376 317 263 167 81 33 3 0


Docetaxel CRPC: Secondary Outcomes
 Secondary outcomes support survival benefit
Response, % MDV3100 Placebo P Value
(n = 800) (n = 399)
PSA decline
 ≥ 50% from baseline 54.0 1.5 < .0001
 ≥ 90% from baseline 24.8 0.9 < .0001
STOR by CT/MRI 28.9 3.8 < .0001
Progression, Mos MDV3100 Placebo HR
(n = 800) (n = 399) (95% CI; P Value)
Median time to PSA 8.3 3.0 0.0248
progression
(0.204-0.303; < .0001)
Median radiographic PFS 8.3 2.9 0.404
(0.350-0.466; < .0001)



Docetaxel CRPC: Toxicity
 Adverse event rates similar for MDV3100 and placebo, despite longer reporting
period for MDV3100
 No on-treatment patient deaths
Treatment-Related AEs, % All Grades Grade ≥ 3 Events
MDV3100 Placebo MDV3100 Placebo
(n = 800) (n = 399) (n = 800) (n = 399)
All AEs 98.1 97.7 45.3 53.1
All serious AEs 33.5 38.6 28.4 33.6
Fatigue 33.6 29.1 6.3 7.3
Cardiac disorders 6.1 7.5 0.9 2.0
 Myocardial infarction 0.3 0.5 0.3 0.5
LFT abnormalities 1.0 1.5 0.4 0.8
Seizure* 0.6 0 0.6 0
*2 of 5 patients experiencing seizure on MDV3100 were found to have brain metastases; 1 was receiving
IV lidocaine for biopsy.


Phase III Study: BMFS With Denosumab in
M0 CRPC With Aggressive PSA Kinetics
Bone metastasis or death
Double-blind randomization

Denosumab 120 mg SC q4w
Patients with M0 (n = 716)
CRPC at high risk for
bone metastases:
PSA ≥ 8.0 ng/mL Calcium and vitamin D Survival
or PSADT ≤ 10.0 mos supplementation Follow-up
(N = 1432) Off investigational
Placebo 120 mg SC q4w product
(n = 716)

 Primary endpoint: bone metastasis-free survival
 Secondary endpoints: time to first bone metastasis (either symptomatic or
asymptomatic), OS

Smith MR, et al. ASCO GU 2012. Abstract 6. Smith MR, et al. Lancet. 2012;379:39-46.


Denosumab in High-Risk M0 CRPC:
Bone Metastasis–Free Survival
 Median BMFS prolonged with denosumab
– Denosumab: 29.5 mos
– Placebo: 25.2 mos
– HR: 0.85 (95% CI: 0.73-0.98; P = .028)
 Robust treatment effect demonstrated in men identified as high-risk by short
PSADT

Median BMFS Denosumab, Mos Placebo, Mos HR (95% CI) P Value
PSADT ≤ 4 mos 25.8 18.3 0.71 (0.56-0.90) .004

PSADT ≤ 6 mos 25.9 18.7 0.77 (0.64-0.93) .006
PSADT ≤ 10 mos 28.4 22.4 0.84 (0.72-0.99) .042

Smith MR, et al. ASCO GU 2012. Abstract 6.


Denosumab in High-Risk M0 CRPC:
Secondary Endpoints
 OS: no improvement with denosumab  Time to first bone metastasis prolonged
vs placebo with denosumab vs placebo
 Fewer symptomatic bone metastases
with denosumab vs placebo

Overall Survival Time to Symptomatic Bone Metastasis
Proportion of Patients

Proportion of Patients
1.0 1.0

Without Symptomatic
Bone Metastases
0.8 0.8
HR: 0.67 (95% CI: 0.49-0.92)
Survived

0.6 0.6 P = .013
HR: 1.01 (95% CI: 0.85-1.20) Risk Reduction
33%
0.4 P = .91 0.4
Events, n (%)
0.2 Placebo 0.2 Placebo 96 (13)
Denosumab Denosumab 69 (10)
0 0
0 6 12 18 24 30 36 42 0 6 12 18 24 30 36
Study Month Study Month

Smith MR, et al. ASCO GU 2012. Abstract 6. Smith MR et al, Lancet. 2012;379:39-46.


CRT vs IMRT vs Proton Therapy for
Localized Prostate Cancer
 Comparison of morbidity and disease control between
conformal radiation therapy, intensity modulated RT, and proton
therapy
– SEER-Medicare data for men diagnosed with localized prostate
cancer after 2002
– CPT codes used to identify men receiving external beam radiation
as initial primary therapy
– Comorbidity scores calculated by NCI Combined Index
– Evaluation of morbidities, posttreatment interventions, and salvage
therapies as surrogate for disease control
– Propensity Score Adjustment used to minimize bias

Sheets NC, et al. ASCO GU 2012. Abstract 3.


Comparative Effectiveness of CRT, IMRT,
PT For Localized Prostate Cancer: Results
 IMRT (n = 6666) vs CRT  IMRT (n = 684) vs PT (n = 684)
(n = 6310) – IMRT: lower incidence of bowel
– Median follow-up: 4.5 yrs morbidity (P < .001)
– IMRT associated with lower – All other morbidity outcomes
incidence of bowel morbidity similar between cohorts
(P < .001) and hip fracture – No difference in need for
(P = .006) subsequent cancer control
– IMRT associated with higher after radiation therapy
incidence of erectile dysfunction
(P = .006)
– IMRT: reduced need for
subsequent cancer therapy
after radiation (P < .001)

Sheets NC, et al. ASCO GU 2012. Abstract 3.


ALSYMPCA: Phase III Trial of Radium-223
in Symptomatic Prostate Cancer
Randomized 2:1
Up to 6 treatments at 4-wk intervals
Radium-223
Patients with (50 kBq/kg)
symptomatic CRPC and +
≥ 2 bone metastases Best standard of care
with no known visceral
metastases, either post- Stratified by total ALP, previous docetaxel,
docetaxel or unfit for and bisphosphonate use
docetaxel
Placebo (saline)
+
(N = 921) Best standard of care

 Primary endpoint: OS
 Secondary endpoints: time to first SRE, time to total ALP progression, total ALP
response, ALP normalization, time to PSA progression, safety, QoL
Parker C, et al. ASCO GU 2012. Abstract 8.


ALSYMPCA: OS With Radium-223
 OS improved significantly
with radium-223 vs
placebo
 Median OS 100
HR: 0.695 (95% CI:
80 0.552-0.875; P = .00185)
– Radium-223: 14.0 mos

Patients (%)
60 Radium-223: n = 541
– Placebo: 11.2 mos 40
Median OS: 14.0 mos

20 Placebo: n = 268
Median OS: 11.2 mos
0
0 6 12 18 24 30 36 36 36 42
Mo
Radium-233 541 450 330 213 120 72 30 15 3 0
Placebo 268 218 147 89 49 28 15 7 3 0



ALSYMPCA: Time to First SRE With
Radium-223
 Median time to first SRE significantly prolonged with radium-223
– Radium-223: 13.5 mos
– Placebo: 8.4 mos
Patients, n (%)
100 First SRE Radium-223 Placebo
HR: 0.610 (95% CI: 0.461-0.807; P Value*
Component
Patients Without SRE

80 P = .00046) (n = 541) (n = 268)
External 122 (23) 72 (27) .0038
Radium-223: n = 541 beam
60
Median OS: 13.5 mos radiotherapy
(%)

40 Spinal cord 17 (3) 16 (6) .016
Placebo: n = 268 compression
20 Median OS: 8.4 mos
Pathologic 20 (4) 18 (7) .013
bone fracture
0
0 3 6 9 12 15 18 21 Surgical 9 (2) 5 (2) .69
intervention
Mo
*Not adjusted for multiplicity
Radium-233 541 379 214 111 51 22 6 0
Placebo 268 159 74 30 15 7 2 0

Sartor O, et al. ASCO GU 2012. Abstract 9.


ALSYMPCA: Toxicity
All Grades Grades 3 or 4
Patients With AEs,
n (%) Radium-223 Placebo Radium-223 Placebo
(n = 509) (n = 253) (n = 509) (n = 253)
Hematologic
 Anemia 136 (27) 69 (27) 54 (11) 29 (12)
 Neutropenia 20 (4) 2 (1) 9 (2) 2 (1)
 Thrombocytopenia 42 (8) 14 (6) 22 (4) 4 (2)
Nonhematologic
 Bone pain 217 (43) 147 (58) 89 (18) 59 (23)
 Diarrhea 112 (22) 34 (13) 6 (1) 3 (1)
 Nausea 174 (34) 80 (32) 8 (2) 4 (2)
 Vomiting 88 (17) 32 (13) 10 (2) 6 (2)
 Constipation 89 (18) 46 (18) 6 (1) 2 (1)



Phase I/II Open-Label Study: Ipilimumab in
Metastatic CRPC
 Men with progressive mCRPC after discontinuation of antiandrogen
therapy, ECOG PS 0/1, and ≤ 1 previous docetaxel therapy (N = 71)
 Dosing schedule
– IPI: every 3 wks up to 4 doses, then every 12 wks if benefit observed
– XRT: 8 Gy/target lesion up to 3 lesions/patient within 24-48 hrs of initial
ipilimumab
– Phase I dose escalation: ipilimumab 3, 5, or 10 mg/kg; then 3 or 10 mg/kg +
XRT (at least 6 patients/cohort)
– Phase II: expansion of ipilimumab 10 mg/kg and 10 mg/kg + XRT cohorts
 Endpoints: safety, response

Slovin SF, et al. ASCO GU 2012. Abstract 25.


Phase I/II Open-Label Study of Ipilimumab
in Metastatic CRPC: Toxicity
 No DLTs observed
 Most treatment-related AEs were grade 1/2 immune-related events,
manageable by corticosteroids, HRT, and supportive control
 Grade 3/4 immune-related AEs in the 10 mg/kg ipilimumab–XRT
cohort
– Grade 3 colitis: 16%
– Grade 3 diarrhea: 8%
– Grade 3/4 hepatitis: 4%/6%
 1 treatment-related death in 5-mg/kg cohort attributed to aspergillosis
after prolonged immunosuppression for grade 3 colitis
 No exacerbation of AEs with addition of XRT to ipilimumab 10 mg/kg

Slovin SF, et al. ASCO GU 2012. Abstract 25.


Phase I/II Open-label Study of Ipilimumab
in Metastatic CRPC: Response
All Treated Patients

 Clinical antitumor activity 400
Day 85
400
At Any Time

Percent Change

Percent Change
300 300
with ipilimumab 10 mg/kg

From Baseline

From Baseline
200 200
alone or with XRT 100 100
0 0
– PSA decline, typically by -100 -100
Day 85 0 10 20 30 40 50 60
Patients (N = 85)
70 0 10 20 30 40 50 60
Patients (N = 85)
70

Ipilimumab 10 mg/kg Alone Cohort
– Soft tissue tumor control 400
Day 85
400
At Any Time

Percent Change

Percent Change
From Baseline

From Baseline
 Response (ipilimumab
10 mg/kg ± XRT) 0 0

– CR: 1 -100 -100
0 3 5 7 9 11 13 15 0 3 5 7 9 11 13 15
– Time to response: 2.5 mos Patients (N = 15) Patients (N = 15)

Ipilimumab 10 mg/kg + XRT Cohort

– SD lasting 2.8-6.1 mos: 6 200
Day 85
200
At Any Time
Percent Change

Percent Change
From Baseline

From Baseline
100 100

0 0

-100 -100
0 10 20 30 0 10 20 30
Slovin SF, et al. ASCO GU 2012. Abstract 25. Patients (N = 30) Patients (N = 30)


Cixutumumab or Ramucirumab + MP in
mCRPC After Progression on Docetaxel
Stratified by ECOG PS,
pain, response on previous Arm A
docetaxel Cixutumumab 6 mg/kg qw
Mitoxantrone 12 mg/m2 q3w
max: 12 cycles
Patients with mCRPC, Prednisone 5 mg PO BID
ECOG PS 0-2, and (n = 66)
disease progression
during or within
120 days after docetaxel
Arm B
(N = 132) Ramucirumab 6 mg/kg qw
Mitoxantrone 12 mg/m2 q3w
max: 12 cycles
Prednisone 5 mg PO BID
(n = 66)

 Primary endpoint: composite PFS
 Secondary endpoints: safety, PFS over time, OS, ORR, PK
Hussain M, et al. ASCO GU 2012. Abstract 97.


mCRPC With PD Post-Docetaxel: Safety
 Cixutumumab and ramucirumab regimens well tolerated in
most patients with docetaxel-resistant CRPC
 Most frequently reported AE: fatigue
 Incidence of most grade 3 or 4 nonhematologic AEs < 10%

Treatment-Emergent Arm A (Cix) (n = 66) Arm B (Ram) (n = 66)
Hematologic AEs, % Any Grade Grade Any Grade Grade
Grade 3 4 Grade 3 4
Neutropenia 40.9 16.7 15.2 37.9 24.2 9.1
Anemia 36.4 4.5 0 36.4 10.6 0
Leukopenia 31.8 16.7 6.1 25.8 15.2 1.5
Thrombocytopenia 19.7 4.5 1.5 34.8 7.6 0



mCRPC With PD Post-Docetaxel: Safety
 Incidence of cardiac dysfunction greater in ramucirumab arm
 No grade 4 or 5 cardiac failures reported

Arm A (CIX) Arm B (RAM)
Cardiac Function: LVEF Results (n = 66) (n = 66)
n % n %
LVEF reduced by > 10% from pretreatment level 8 12.1 22 33.3
Baseline LVEF ≥ 70% + LVEF decrease by > 10%, 3 4.5 4 6.1
to level ≥ 55%
LVEF decreased to ≤ 35% 1 1.5 5 7.6
AE of LV dysfunction, reduced LVEF or CHF 8 12.1 15 22.7
AE of LV dysfunction, reduced LVEF or CHF: grade 3 0 0 5 7.6
Discontinuation of any study therapy due to reduced 6 9.1 11 16.7
LVEF or CHF


mCRPC With PD Post-Docetaxel: Efficacy
 Moderate disease control in mCRPC with cixutumumab or
ramucirumab in combination with mitoxantrone and prednisone
– Cixutumumab
– Median cPFS: 4.1 mos (95% CI: 3.0-5.6)
– Preliminary median OS: 10.8 mos
– 1-yr survival: 41.6%
– Ramucirumab
– Median cPFS: 6.7 mos (95% CI: 4.5-8.3)
– Preliminary median OS: 13.0 mos
– 1-yr survival: 54.2%



First-Line OGX-427 + Prednisone vs
Prednisone in mCRPC
 OGX-427: synthetic oligonucleotide inhibitor of Hsp27 gene expression

OGX-427 600 mg IV x 3. loading doses
Patients with within 10 days, then 1000 mg IV weekly +
progressive mCRPC Prednisone 5 mg PO BID
who received no prior
chemotherapy for
metastatic disease

(N = 33) Prednisone 5 mg PO BID*

*Crossover allowed upon disease progression
 Primary endpoint: PD at 12 wks
 Secondary endpoints: PSA decline, measurable disease response, PFS, TTP,
CTC count, serum/plasma HSP27
Chi KN, et al. ASCO GU 2012. Abstract 121.


OGX-427/Prednisone in mCRPC: Results
Outcome, n (%) OGX-427/Prednisone Prednisone
Disease progression at 12 wks (n = 14) (n = 12)
 No disease progression 10 (71; 95% CI: 42% to 92%) 4 (33; 95% CI: 10% to 86%)
 Disease progression 4 (29) 8 (67)
Best PSA decline from baseline (n = 17) (n = 16)
 ≥ 80% 2 (12) 1 (7)
 ≥ 60% 7 (41) 3 (20)
 ≥ 30% 10 (69) 6 (33)
 Any 13 (78) 8 (53)
Measurable disease response (n = 8) (n = 9)
 PR 3 (38) 0
 SD 1 (13) 4 (44)
 PD 0 2 (22)
Best CTC change from baseline, per 7.5 mL (n = 14) (n = 12)
 ≥ 5 to < 5 7 (50) 4 (31)
 < 5 to < 5 1 (7) 1 (8)
 ≥ 5 to ≥ 5 6 (43) 8 (61)



OGX-427/Prednisone for mCRPC: Toxicity
Incidence of All Laboratory OGX-427 + Prednisone Prednisone
Treatment-Emergent Events
(n = 17) (n = 15)
Grade 1/2 Grade 3/4 Grade 1/2 Grade 3/4
All, % 76% 24% 80% 20%
Lymphopenia, n 10 3 12 2
Anemia, n 12 0 10 0
Hyperglycemia, n 12 1 7 1
Elevated creatinine, n 3 1* 6 0
Elevated AST/ALT, n 9 0 0 0
Thrombocytopenia, n 6 1 2 0
Hyponatremia, n 3 1 2 0
Hypokalemia, n 4 0 2 0
*1 case of grade 4 hemolytic uremic syndrome reported at Wk 7.



Phase II Study: Personalized DC-Based
Therapy (AGS-003) + Sunitinib for mRCC
 AGS-003: fully personalized immunotherapy
– RNA-loaded DCs
– Stimulates tumor-targeted cytotoxic T lymphocyte proliferation

Newly diagnosed
adults with advanced Pretreatment Treatment Booster
stage RCC, ECOG
PS 0-1, who had no
Diagnosis Sunitinib AGS-003 AGS-003
previous systemic
therapy Screening 1 cycle* 5 doses, quarterly
Nephrectomy 3 wks apart until PD
(N = 21) Leukapheresis *6-wk cycles:
4 wks on, Sunitinib continuing until PD
2 wks off

 Primary endpoint: objective tumor response (RECIST)
 Secondary endpoints: CBR, OS, PFS, immune response, and safety
Figlin RA, et al. ASCO GU 2012. Abstract 348.


AGS-003 + Sunitinib in mRCC: Efficacy
 PR: 8 (38%); 3 after prolonged booster phase  Median PFS: 11.2 mos
 CBR (PR + SD): 13 (62%)  Median OS: 29.3 mos (Kaplan-Meier)
 Immunologic response: 11/15 (73%) Induction of CD28+CD45RA- T Cells
Correlates* With OS
OS by Subject (N = 21) 300
621 1841
% Change in 250
Effector/Memory 200
*Patients ongoing without progression T Cells Between 150
Baseline and Fifth100
= Alive in active OS follow-up
AGS-003 Dose 50 0
-50
-100
1 2 3 4 5 6 7 8 9 10 11 12 13 14 15
Subject

Registration (Mos)
* 40 = Alive in active follow up
* 35
*
OS From
30
25
20
16
10
5
0 5 10 15 20 25 30 35 40 0
OS From Registration (Mos) 1 2 3 4 5
6 7 8 9 10 11 12 13 14 15
Subject
3 subjects remain on study protocol without PD; 8 subjects still alive; *Highly significant by nonparametric bivariate analysis (P = .0061)
9 subjects (43%) experienced OS > 30 mos


AGS-003 + Sunitinib in mRCC: Safety
 21 subjects have received > 150 doses of AGS-003
 No AGS-003–related grade 3/4 AEs reported; grade 3/4
hematologic AEs attributable to sunitinib included leukopenia
(8%), anemia (4%), and thrombocytopenia (4%)
 Grade 1 AEs attributable to AGS-003 included injection-site
erythema and injection-site induration, occurring in 33.3% and
23.8% of subjects, respectively
 All other observed AEs consistent with previous findings for
sunitinib in advanced RCC
 No emergent autoimmune disease observed



Phase II MET111644 Study: Foretinib in
Patients With Papillary RCC
 Multicenter, prospective phase II and biomarker, open-label, single-stage study

Patients with confirmed Intermittent Cohort
sporadic or hereditary Foretinib 240 mg/day, Days 1-5 every 14 days
papillary RCC, ECOG
PS 0-2, and ≤ 1
previous systemic Stratified by MET mutation status
therapy
Daily Cohort
(N = 74) Foretinib 80 mg/day

 Primary endpoint: ORR by RECIST 1.0
 Secondary endpoints: PFS, OS, safety, correlation of outcome with PK, PD,
MET

Choueiri TK, et al. ASCO GU 2012. Abstract 355.


MET111644: Foretinib Efficacy
Outcome Intermittent Dosing Daily Dosing Total
(n = 37) (n = 37) (N = 74)
ORR n (%) 5 (13.5) 5 (13.5) 10 (13.5)
DOR: 18.5 mos
Disease stabilization rate (ORR + SD): 88%
Median PFS, mos 11.6 9.1 9.6
Median OS Not reached Not reached Not reached
1-yr OS, % 64 76 70

 Evidence of tumor shrinkage in 50/68 evaluable patients
 Significant modulation of VEGF, HGF, sMET, sVEGFR2 suggestive of MET
pathway inhibition in both arms; not strongly correlated with outcomes



MET111644: Foretinib Toxicity
Treatment-Related Toxicity All Grades, Grade 3/4,
(N = 74) n (%) n (%)
Hypertension 60 (81.0) 38 (51.0)
Fatigue 45 (73.0) 5 (7.0)
Diarrhea 41 (55.0) 7 (9.5)
Laboratory toxicities (≥ 10%)
 Hypophosphatemia 17 (23.0) 0
 Proteinuria 16 (22.0) 4 (5.0)
 Increased lipase 14 (19.0) 7 (9.5)
 ALT elevation 13 (17.0) 1
 AST elevation 13 (17.0) 2 (3.0)
 Hypothyroidism 12 (16.0) 0
 Thrombocytopenia 8 (11.0) 1 (1.4)



AXIS: Axitinib vs Sorafenib in Refractory
mRCC, Secondary Analyses[1]
Stratified by ECOG PS and
type of previous treatment

Patients with clear-cell Axitinib 5 mg BID*
mRCC progressing after (n = 361)
1 previous systemic first-
line regimen including *Starting dose 5 mg BID with option for
sunitinib, bevacizumab + dose titration to 7 mg BID, then to a maximum
IFN-α, temsirolimus, or of 10 mg BID.
cytokines
Sorafenib 400 mg BID
(N = 723) (n = 362)

 Primary endpoint: PFS significantly prolonged with axitinib vs sorafenib[2]
– Median PFS with axitinib vs sorafenib: 6.7 mos (95% CI: 6.3-8.6) vs 4.7 mos (95% CI: 4.6-5.6);
HR: 0.665 (95% CI: 0.544-0.812; P < .0001)
 Secondary analyses: effect of dose titration and previous first-line treatment duration and
response on axitinib efficacy
1. Rini BI, et al. ASCO GU 2012. Abstract 354^. 2. Rini BI, et al. Lancet. 2011;378:1931-1939.


AXIS Results: Patient Disposition
Starting dose
5 mg BID
N = 359
Highest titration to 7 mg BID
(100%)
n = 60 (17%)

Mean duration (7 mg/BID): Dose
Dose 92 days reduction
No dose Dose after
reduction
change escalation increase
< 5 mg Highest titration to 10 mg BID
5 mg BID > 5 mg BID n = 71 (20%)
BID n = 71 (20%)
n = 139 n = 132
n = 88
(39%) (37%) Mean duration (10 mg/BID):
(25%)
127 days

Rini BI, et al. ASCO GU 2012. Abstract 354^.


AXIS Dose Titration Analysis: Results
 PFS similar with axitinib
≤ 5 mg BID and > 5 mg BID; Progression-Free Survival
both superior to PFS with
1.00
sorafenib

Survival Distribution Function
Axitinib ≤ 5 mg BID
 Incidence of AEs similar Axitinib > 5 mg BID
with axitinib ≤ 5 mg BID 0.75 Sorafenib
and > 5 mg BID
– Slightly increased in dose- 0.50
titrated patients: nausea,
asthenia, decreased
appetite 0.25

– Slightly decreased in
dose-titrated patients: 0
hypothyroidism, proteinuria, 0 2.5 5.0 7.5 10.0 12.0 15.0 17.5 20.0
hypertension Mos



AXIS: PFS by Previous Response to
Sunitinib
Axitinib Sorafenib
 PFS similar with axitinib mPFS, mPFS,
≤ 5 mg BID and > 5 mg BID; n Mos 95% CI n Mos 95% CI
Nonresponders 145 4.8 4.2-6.7 Nonresponders 143 3.0 2.8-4.6
both superior to PFS with Responders 47 4.6 2.8-6.3 Responders 52 4.7 2.9-6.6
sorafenib 1.00 1.00

 Trend toward increased PFS 0.80 0.80
for patients receiving sunitinib

Probability PFS

Probability PFS
for > 9 mos 0.60 0.60

 Previous objective response 0.40 0.40
on sunitinib not correlated to
PFS with axitinib 0.20 0.20

0 0
0 2 4 6 8 10 12 14 16 18 20 0 2 4 6 8 10 12 14 16 18 20
Mos Mos

PFS by Duration of Previous Sunitinib, Mos (95% CI; n)
Agent
< 3 vs ≥ 3 mos < 6 vs ≥ 6 mos < 9 vs ≥ 9 mos
Axitinib 4.5 4.8 4.6 4.8 4.5 6.3
(2.7-NR; 22) (4.5-6.5; 170) (2.8-8.3; 48) (3.6-6.5; (2.8-6.4; 90) (4.6-6.7; 102)
Sorafenib 2.8 3.7 2.8 4.6
144) 2.9 4.6
(1.4-15.7; (2.8-4.7; 173) (1.6-3.7; 62) (2.9-4.9; (2.8-4.6; 87) (2.9-4.9; 107)
21) 132)


Long-term Outcomes After Radiotherapy
for Stage II Testicular Seminoma
 Patients with stage II testicular seminoma given RT at Mayo Clinic between 1974-2007:
N = 49
– Median age at diagnosis: 35 yrs (range: 22-71)
– CT staging (AJCC 7th edition) available for 46 patients
– IIA: 23 (47%); IIB: 7 (14%); IIC: 15 (31%); II NOS: 4 (8%)

– 3 patients: RT for PA recurrence after stage I seminoma
– 4 patients: RT and chemotherapy due to bulky disease

 Abdominal/pelvic RT field  Median infradiaphragmatic RT dose:
30.4 Gy (range: 13.3 - 44.7)
– PA + bilateral pelvis: 25 (51%)
 Prophylactic MSCV RT: 24 (49%)
– PA + ipsilateral pelvis: 21 (43%)
– PA only: 3 (6%)  Median MSCV RT dose: 20 Gy
(range: 12-30)

Hallemeier CL, et al. ASCO GU 2012. Abstract 327.


Long-Term Outcomes After RT for Stage II
Testicular Seminoma
Outcome Patients Relapse-Free Survival Estimates (KM)
1.00

Relapse-Free Survival
IIA
10/20-yr OS, % 94/81 0.8
(n = 23)

10/20-yr CSS, % 96/96 0.6
IIC
(n = 15)
Recurrence, n (%) 9 (18)* 0.4 IIB
(n = 7)
 MSCV regions, n 6 0.2
P = .37
 PA nodes, n 1 0
0 5 10 15 20
 Lung parenchyma, n 1
Yr
 Peritoneal cavity, n 1
Relapse Risk Estimates (KM)
Major cardiac events, n (%) 10 (20) 1.00
P = .04
Second malignancy, n (%) 5 (10) 0.8

Relapse
0.6 IIB, no MSCV RT (n = 7)
*7 of 9 recurrences successfully salvaged with chemotherapy.
0.4
 Risk of MSCV failure significantly associated with IIA, no MSCV RT (n = 13)
0.2
intradiaphragmatic RT alone, particularly in stage IIB
IIA/B MSCV RT (n = 11)
0
 MCE, SM occurred at median 18 yrs (range 7-30), 0 5 10
27 yrs (range 20-34) post-RT, respectively Yr
Hallemeier CL, et al. ASCO GU 2012. Abstract 327.


BCL2L1 and TACC3 SNPs Associated With
BCG Response in Nonmuscle-Invasive BC
 Genotyping study: can SNPs predict response to BCG intravesical therapy in
nonmuscle-invasive bladder cancer?
 Patients with NMIBC who received 6 doses of BCG (± maintenance) as
first-line therapy postresection (N = 158)
– Genotyping with 80 SNPs selected from published studies
– Urothelial cancer risk
– DNA damage repair
– Inflammation
– Immune reactions
– Anonymous linking of genotype and response data
– Determination of association between each SNP and BCG response
 Results tested in an independent patient cohort (N = 168)

Alanee S, et al. ASCO GU 2012. Abstract 260.


BCL2L1 and TACC3 SNPs Associated With
BCG Response in NMIBC: Results[1]
 2 SNPs significantly associated with BCG response by multivariate analysis
(n = 158)
– rs798766 inTACC3 (OR: 3.4; P = .01)
– rs1994251 in BCL2L1 (OR: 3.2; P = .02)
– Validation confounded by institutional variation in treatment outcome
 12 SNPs previously reported as predictive of BCG response not validated
 Analysis of a cohort controlled for confounders (N = 276) revealed 1 SNP
predictive of refractory disease, not previously associated with BCG
– rs11615 in ERCC
– Nucleotide excision repair pathway
– Associated with cisplatin cytotoxicity in gastric, ovarian, colorectal cancers[2,3]
– 33% of patients with CC genotype of rs11615 were BCG refractory vs 11% with TT
genotype (OR: 1.8; 95% CI: 1.14-3; P =.01)

1. Alanee S, et al. ASCO GU 2012. Abstract 260. 2. Smith S, et al. J Clin Oncol. 2007;25:5172-5179.
3. Gangawar R, et al. Med Oncol. 2010;27:159-166.


Pooled Analysis of Long-term Outcomes
in MIBC After Bladder-Preserving CMT
 Pooled analysis (N = 468) of long-term outcomes from
RTOG studies of combined-modality therapy for muscle-
invasive bladder cancer
– Phase II: RTOG 8802, 9506, 9706, 9906, and 0233
– Phase III: RTOG 8903
 OS estimated by Kaplan-Meier method
 DSS, local failure, and distant metastases estimated by
cumulative incidence method
 Clinical variables associated with DSS identified by Fine
and Gray’s proportional hazard regression model

Mak RH, et al. ASCO GU 2012. Abstract 264.


Pooled Analysis of Long-term Outcomes
in MIBC After Bladder-Preserving CMT
 Long-term outcomes with bladder-preserving CMT comparable to
outcomes reported for previous single-institution series

 Decreased OS, DSS associated  Improved DSS associated with
with higher clinical stage complete response to CMT

100
Clinical OS DSS 78.8%
Stage, %

Disease-specific
(P = .002) (P = .05) 75

Survival (%)
56.0%
5 Yr 10 Yr 5 Yr 10 Yr
50
T2 62 41 74 69 Failed Total
25 Complete responders 78 321
T3/T4 49 30 66 60 Nonresponders 59 125
P < .0001
0
0 1 2 3 4 5
Yrs After Randomization
Patients at Risk, n
Complete responders 321 299 258 225 190 164
Nonresponders 125 104 77 54 49 40
Mak RH, et al. ASCO GU 2012. Abstract 264.


Neoadjuvant DD-MVAC + Bevacizumab in
High-Risk Urothelial Cancer: Phase II Trial
 Patients with bladder cancer or upper tract tumor: N = 60
 Dosing regimen
– Bevacizumab 10 mg/kg, then
– Methotrexate 30 mg/m2 + vinblastine 3 mg/m2 + doxorubicin 30 mg/m2 +
cisplatin 70 mg/m2 (DD-MVAC)
– Agents given over Days 1-2, every 2 wks with 3L mannitol infusion and IV
pegfilgrastim
– 4 cycles of therapy
 Surgery minimum of 6 wks after last bevacizumab dose
 Primary endpoint: pathologic down-staging to ≤ pT1N0
 Secondary endpoints: OS, DSS, tolerability

Siefker-Radtke AO, et al. ASCO GU 2012. Abstract 261.


High-Risk Urothelial Cancer: Results
Survival at Median Follow-up of 26 Mos, OS DSS
% 2 Yr 3 Yr 2 Yr 3 Yr
All patients 78 63 82 64
Bladder/urethra (n = 44) 75 52 78 54
Upper tract (n = 16) 93 93 93 93

 Significant improvement in OS, DSS DSS by pStage
with down-staging to ≤ pT1N0M0 1.0
0.9
 Down-staging to ≤ pT1N0: 53% Relapse-Free Survival
0.8
– Bladder/urethra: 45% 0.7
0.6
– Upper tract: 75% 0.5
 Down-staging to ≤ pT0N0: 38% 0.4 3 Yr
OS DSS Med
0.3 pStage T0-T2N0 97% 97% NR
– Bladder/urethra: 39% 0.2 pStage T3b-T4aN0 66% 83% NR
pStage T4b, N+ or M+ 24% 24% 17 mos
– Upper tract: 38% 0.1 P = .00026
0
0 12 24 36 48 60
Survival Time (Yr)


High-Risk Urothelial Cancer: Tolerability
 Chemotherapy
– Patients completing 4 cycles of chemotherapy: 51 (85%)
– Grade 3 or 4 neutropenia or neutropenic fever: 17% and 4%, respectively
– Grade 3 mucositis: 3%

 Surgery
– Cystectomy: 43 –Nephrectomy/nephroureterectomy:
– Median hospital stay: 9 days 16
– Hospital stay > 11 days: 23% – Median hospital stay: 4 days
– Hospital stay > 11 days: 13%


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